Hypercholesterolemia is known to be one of the prime risk factors for ischemic cardiovascular disease, such as arteriosclerosis. Bile acid sequestrants have been used to treat this condition; they seem to be moderately effective but they must be consumed in large quantities, i.e. several grams at a time and they are not very palatable.
MEVACOR.RTM. (lovastatin) and ZOCOR.RTM., now commercially available, are members of a group of very active antihypercholesterolemic agents that function by limiting cholesterol biosynthesis by inhibiting the enzyme HMG-CoA reductase.
Squalene synthase (also called squalene synthetase) is the enzyme involved in the first committed step of the de novo cholesterol biosynthetic pathway. This enzyme catalyzes the reductive dimerization of two molecules of farnesyl pyrophosphate to form squalene. The inhibition of this committed step to cholesterol should leave unhindered biosynthetic pathways to ubiquinone, dolichol and isopentenyl t-RNA.
Previous efforts at inhibiting squalene synthase have employed pyrophosphate or pyrophosphate analog containing compounds such as those described in P. Ortiz de Montellano et al., J. Med. Chem. 20, 243 (1977), E. J. Corey and R. Volante, J. Am. Chem. Soc., 98, 1291 (1976), and U.S. Pat. No. 5,025,003 to S. Billet. U.S. Pat. No. 4,871,721 to S. Billet describes isoprenoid(phosphinylmethyl) phosphonates as inhibitors of squalene synthase.
U.S. Pat. Nos. 5,096,923; 5,026,554; and 5,102,907 disclose non-phosphorus-containing substituted 2,8-dioxabicyclo-[3.2.1]octane derivatives useful as squalene synthase inhibitors.
Recently it has been shown that certain natural product nonphosphorous containing inhibitors of squalene synthase and their esters are useful in inhibiting fungal growth. This utility is described in U.S. Pat No. 5,026,554.
The present invention is directed to compounds of structural formula (I) which are squalene synthase inhibitors for the inhibition of fungal growth.
The present invention is also directed to compounds of structural formula (I) which are inhibitors of farnesyl-protein transferase for inhibition of farnesylation of the oncogene protein Ras and the treatment of cancer.
These compounds are inhibitors of farnesyl-protein transferase. Farnesyl-protein transferase utilizes farnesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a farnesyl group. Inhibition of farnesyl pyrophosphate biosynthesis by inhibiting HMG-CoA reductase blocks Ras membrane localization in vivo and inhibits Ras function. Inhibition of farnesyl-protein transferase is more specific and is attended by fewer side effects than is the case for a general inhibitor of isoprene biosynthesis.
Previously, it has been demonstrated that tetrapeptides with the CAAX sequence inhibit Ras farnesylation (Schaber et al., ibid: Reiss et. al., ibid; Reies et al., PNAS, 88:732-736 (1991)). However, the reported inhibitors of farnesyl-transferase are metabolically unstable or inactive in cells.
Pharmaceutical compositions containing the compounds of this invention and methods of treatment utilizing these compositions for use in inhibiting farnesyl-protein transferase and farnesylation of the oncogene protein Ras are described herein.
The present invention provides nonphosphorus containing inhibitors of squalene synthase.